DNA methylation is a post replicative chemical modification of DNA. Different cancers can be stratified by their abnormal DNA methylation profiles (degree of global or specific DNA methylation) and the hypermethylation of specific genes can be associated with the prognosis for gastric, lung, esophageal, pancreatic, and colon cancer. DNA methylation patterns can also be used to predict response or resistance to therapy in glioma and melanoma. Azacitidine and decitabine are two FDA approved hypomethylating agents (HMAs) that exert their therapeutic effect by inhibiting DNA methylation levels.
Dinucleotide compounds derived from decitabine for the development of therapies for similar indications have been described in U.S. Pat. No. 7,700,567 and its equivalent WO2007041071. Drug formulations containing dinucleotide compounds of the type described in WO2007041071 are disclosed in WO2013033176. The disclosure in each of U.S. Pat. No. 7,700,567, WO2007041071 and WO2013033176 is incorporated by reference in its entirety.
Lyophilization, often referred to as freeze drying, is a method of dehydration in which a solvent-containing substrate is frozen and then subjected to a vacuum so that the solvent is removed by sublimation, i.e. direct conversion from the the solid frozen state into the gaseous state.